Visual Loss Due to Progressive Multifocal Leukoencephalopathy In

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

but there was a single nucleotide visible, fine-linear white scarring in Visual Loss Due to substitution (C155T) in exon 1 of this area (Figure 2). In the most se- Progressive Multifocal the WAS gene. verely affected gyri, the cortex was Leukoencephalopathy Six weeks later his vision was bi- also involved and had a darker color, in a Congenital lateral finger counting. A magnetic with apparent expansion and soften- resonance imaging (MRI) scan ing of its affected parts. Immunodeficiency Disorder showed scattered areas of white- Although the individual le- matter foci, predominantly peri- sions were present throughout the A 20-year-old man with Wiskott- pheral and not periventricular, on cerebral hemispheres, they were Aldrich syndrome (WAS) initially de- proton density and T2-weighted most frequent bilaterally in the oc- veloped a mild visual disturbance that scans. He was given intravenous cipital poles, which were also the progressed to blindness, increasing methylprednisolone sodium succi- major site of linear cortico–white- neurological deficits, and death nate because of the possibility of de- matter junction lesions and scar- within 4 months. Wiskott-Aldrich myelination. No improvement oc- ring as well as the regions of diffuse syndrome is an X-linked immuno- curred, and he was registered as blind. cortical involvement. A microsco- deficiency disorder characterized by Reduced sensation and generalized pic examination of the brain sec- thrombocytopenia, eczema, and sus- mild weakness (level 4-5) devel- tions showed small, spherical, white ceptibility to infection.1 This case il- oped in his right-hand side and face. matter lesions that were atypical of lustrates the difficulties in reaching Reflexes were normal and he had no PML because they were associated the final diagnosis of progressive mul- dysphasia. with a considerable perivascular and tifocal leukoencephalopathy (PML) A repeat MRI scan showed an in- parenchymal inflammatory infil- in this individual and its unusual his- crease in the number of small high- trate (Figure 3). The inflamma- topathologic features. signal foci together with more con- tory infiltrate was mostly lympho- fluent areas of high signal intensity cytic in character but also contained Report of a Case. A 20-year-old and a scalloped edge in the left oc- plasma cells that were occasionally white man with WAS had a 1-month cipital region (Figure 1). Rapid de- binuclear. However, further exami- history of decline in vision. Nine terioration occurred with protracted nation indicated the presence of di- months previously, he had omitted focal seizures, total blindness, loss of agnostic enlarged magenta-colored 3 consecutive doses of immunoglob- consciousness, and death. A postmor- oligodendrocyte nuclei around the ulin, which he had been receiving tem histopathologic examination of periphery of the foci of demyelin- every 3 weeks since the age of 12 the brain revealed the papovavirus ation, containing the papovavirus years. This was restarted when he de- particles associated with PML. particles associated with PML veloped lethargy and malaise. His The fresh brain was examined (Figure 4). Other differences from mother had been diagnosed with and then prepared in slices. Tissue un- typical examples of PML were that multiple sclerosis at age 26 years. derwent light microscopic examina- the pleomorphic astrocytic reac- An ophthalmological examination and was embedded in paraffin tion within the lesions was less florid tion revealed a visual acuity of 20/17 wax, sectioned, and stained with he- and that foamy macrophages were OD and 20/20 OS with normal pu- matoxylin-eosin. The brain weighed not as conspicuous, although there pillary reactions. Color vision was ab- 1570 g. External examination showed were numerous mononuclear cells normal, and visual field testing mild diffuse vascular congestion but within the larger lesions. In a few showed bilateral enlarged blind spots no focal lesions. Brain slices had large cases the isolated lesions had the with paracentral scotomata. Fundi numbers of small, gray, circular le- character of “burnt-out” lesions, appeared grossly normal. Results of sions in the white matter that were 1 with no enlarged oligodendro- fundus fluorescein angiography were to 3 mm in diameter, many of which cytes, no significant inflammatory re- unremarkable. Electrodiagnostic were close to the cortico–white- action, and a predominantly fi- evaluation was normal apart from de- matter junction. In some cases the le- brous gliosis. The linear lesions in layed visual evoked potentials, which sions were also visible within the cor- the cortico–white-matter junction were suggestive of demyelination. tical ribbon. The lesions had the had the same histological character- The patient’s biochemistry and appearance of small regions of demy- istics as the spherical lesions. The complete blood cell count were nor- elination and resembled the indi- diffuse cortical lesions showed de- mal except for a low platelet count vidual lesions of PML. In addition to myelination within the cortex and (12ϫ103/µL). Mutational analysis the spherical lesions, there were also reactive astrocytosis extending for Leber hereditary optic neuropa- irregular linear lesions along the cor- through the neuropil and around the thy and for the WAS protein gene tico–white-matter junction that in neurons, although no enlarged oli- demonstrated no Leber mutation, some instances were accompanied by godendrocyte nuclei were identi-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Figure 1. Second magnetic resonance imaging scan (17 weeks after initial Figure 2. Fresh brain slices showing large numbers of small, gray, circular symptoms) showing an increase in the number of small high signal foci with lesions in the white matter close to the cortico–white-matter junction (white more confluent areas of high signal intensity, a scalloped edge in the left arrows). Also seen are irregular linear lesions along the cortico–white-matter occipital region, and a serpiginous scalloped appearance at the gray junction (black arrowheads). matter/white matter interface involving the arcuate fibers.

Figure 3. Microscopic picture showing small, spherical, white matter lesions Figure 4. Microscopic section showing the presence of diagnostic enlarged with marked vascular prominence and parenchymal infiltrate homogenous oligodendrocyte nuclei, which contain the papovavirus particles (hematoxylin-eosin, original magnification ϫ20). associated with progressive multifocal leukoencephalopathy (arrows) at the periphery of the focus of demyelination (hematoxylin-eosin, original magnification ϫ100).

fied within the affected regions of the hereditary optic neuropathy or the sclerosis,2 electrodiagnostic test re- cortical ribbon. possibility of a contiguous deletion in sults were was suggestive of optic the same region as the WAS gene, nerve demyelination. Visual distur- Comment. Delay in the diagnosis of leading to a phenotypic complex of bance in multiple sclerosis is almost PML was probably due to visual WAS and perhaps an X-linked cone always due to optic nerve rather than symptoms dominating this case, late dystrophy, were explored and ex- cortical involvement. The reverse is development of neurological signs, cluded. true for PML. Despite increasing cen- and the outstanding longevity and Although the lesions that ap- tral scotomata, the preserved pupil- relative good health of the patient. In- peared on the initial MRI scan were lary reflexes should have directed us herited conditions including Leber not completely typical of multiple earlier to a cortical etiology. Typical

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 PML features became more identi- At the time of referral 6 days fiable by the second MRI scan Complication From Use later, the patient’s visual acuity was (Figure 1). The histopathologic char- of Alcohol to Treat 20/200 with pinhole approxima- acteristics of this case include an un- Epithelial Ingrowth tion, and she had a large central epi- usual variant of PML: there was a thelial defect. The edematous flap After Laser-Assisted marked inflammatory response, and made the interface difficult to exam- the demyelinating lesions had an un- In Situ Keratomileusis ine. Her epithelial defect improved usual distribution. The inflamma- during the next week with conser- tory response was presumably a re- Epithelial ingrowth occurs in up to vative treatment, and her visual ac- flection of the immune status of this 4.3% of patients following laser- tivity improved to 20/80 with pin- 1 patient. Whereas most cases of PML assisted in situ keratomileusis. Treat- hole approximation. Four days later, are associated with immune sup- ment varies from observation to lift- the patient returned with 80% melt- pression, no matter what the cause, ing the flap and scraping away the ing of the flap (Figure 1). The re- this case is unusual because a epithelium. With recurrence, addi- maining nasal and temporal pieces of marked inflammatory response was tional treatment options include the the flap were removed and sent to the noted.3,4 A study of ophthalmic signs use of an excimer laser, cocaine, pro- pathology department (Figure 2). in patients with acquired immuno- paracaine hydrochloride, or alcohol deficiency syndrome and PML stated on the stromal bed and flap and su- Comment. Many theories exist re- that bilateral occipital lobe PML may turing the abnormal flap edge. Stud- garding the source of the epithelial lead to cortical blindness, which ap- ies on the efficacy of these interven- cells in epithelial ingrowth, but most pears to be a relatively common tions are lacking. We report a case of researchers believe that the cells event but has received inadequate total flap melting following alcohol grow under the flap from the kera- recognition.5 The initial features of application to the interface to treat re- totomyincision. The factors that this case offer a useful model for current epithelial ingrowth. stimulate or allow this growth are other immunodeficiencies in which not known, but poor adhesion of the patients experience loss of vision and Report of a Case. A 52-year-old flap may be an important factor. neurological signs. woman underwent bilateral laser- When treating epithelial ingrowth, assisted in situ keratomileusis for Susan M. Downes, MD, FRCOphth moderate myopic astigmatism. Post- Oxford, England operatively the patient had irritation and focal flap edema in her left eye Graeme C. M. Black, PhD that persisted for 6 months before Manchester, England epithelial ingrowth was noted. The Nigel Hyman, FRCP patient’s flap was lifted, scraped, and Mike Simmonds, FRCR irrigated 8 months postoperatively. Reading, England Twelve days later, recurrent epithelial James Morris, FRCPath ingrowth was observed. The retreat- Oxford ment consisted of elevating the flap, Carol Barton, FRCPath scraping the stromal bed and flap un- Reading dersurface, applying absolute alcohol on a 6-mm sponge to the stromal bed Corresponding author: Susan M. and flap undersurface twice for 10 sec- Figure 1. Remaining flap attached to nasal hinge Downes, MD, FRCOphth, Oxford onds, and irrigating the interface. after flap melting. Eye Hospital, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, England (e-mail: susan.downes @ophthalmology.oxford.ac.uk).

1. Standen GR. Wiskott-Aldrich syndrome: new perspectives in pathogenesis and management. J R Coll Physicians Lond. 1988;22:80-83. 2. Whiteman ML, Post MJ, Berger JR, Tate LG, Bell MD, Limonte LP. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic cor- relation. Radiology. 1993;187:233-240. 3. Hedley-Whyte ET, Smith BP, Tyler HR, Peter- son WP. Multifocal leukoencephalopathy with remission and five year survival. J Neuropathol Exp Neurol. 1966;27:107-116. 4. Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin. 1984;2:299-313. 5. Omerod LD, Rhodes RH, Gross SA, Crane LR, Kenneth WH. Ophthalmologic manifestations of acquired immune deficiency syndrome– associated progressive multifocal leukoencephalopathy. Ophthalmology. 1996;103:899- Figure 2. Hematoxylin-eosin stain of laser-assisted in situ keratomileusis flap with irregular epithelium 906. (top) and epithelial ingrowth under the flap (bottom). Note the Bowman layer for orientation.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 complete removal or death of all of gery. Recently, 4 cases of spontane- asoft-tipdiamond-dustedsiliconecan- the cells is important to prevent reous resolution of retinal detach- nula, and intravitreal 14% perfluoro- currence. When initial scraping and ment following macular hole surgery propane gas tamponade. The poste- irrigating fails, additional mea- were reported. The authors pro- rior hyaloid membrane was extremely sures such as the use of an excimer posed several possible mechanisms adherent to the disc, and multiple at- laser or alcohol on the stromal bed for postsurgical retinal detachment in tempts were required to separate it in and flap have been attempted. Al- the absence of a clinically detectable this location. No adjuvant for hole clo- cohol has been used in photorefrac- retinal break. We present the first re- sure was used. Careful examination tive keratectomy for many years to port, to our knowledge, of a patient of the peripheral retina was performed remove the epithelium.2 However, with concurrent peripheral annular immediately prior to the fluid-air ex- some reports show that alcohol can choroidal and inferior bullous reti- change, identifying no disease. Intra- induce keratocyte death and in- nal detachment noticed 1 week af- ocular pressure 2 and 4 hours postop- crease inflammation compared with ter macular hole surgery. After ob- eratively was 19 and 21 mm Hg, re- mechanical debridement.3 servation for 7 weeks, both resolved spectively. On postoperative day 1 the Use of alcohol in this case may spontaneously. This case provides vitreouscavitywasfilled80%withgas, have influenced flap adhesion in sev- evidence that the cause of retinal de- the retina appeared flat, and intraocu- eral ways, allowing aggressive epi- tachment after macular hole sur- lar pressure was 21 mm Hg. thelial ingrowth to occur with sub- gery may be exudative. One week later, the patient re- sequent flap melting. First, the Macular holes in stage 2, 3, or 4 ported no new symptoms and was no- alcohol may have caused kerato- are now widely managed with pars ticed to have a 360° peripheral annu- cyte death on both the flap and plana vitrectomy, posterior hyaloid lar choroidal detachment of moder- stroma, which can affect the inter- peeling, and intravitreal perfluoro- ate height accompanied by an inferior action and wound healing of these carbon gas tamponade.1 Complica- bullous retinal detachment extending 2 surfaces. Second, the alcohol may tions of macular hole surgery in- from the 4- to the 8-o’clock position have inadvertently touched the sur- clude cataract, retinal pigment with shifting subretinal fluid. The vit- face epithelium, leading to the epi- epithelial changes, visual field loss, en- reous cavity was filled 60% with gas. thelial defect, flap edema, and poor dophthalmitis, choroidal neovascu- No peripheral retinal tears were seen. flap adhesion. Because there is a lack larization, cystoid macular edema, and The patient continued receiving topi- of basic and clinical research evalu- retinal detachment.2,3 The latter has cal 1% prednisolone acetate 4 times ating alcohol in the treatment of epi- been recognized to occur secondary a day. Two weeks later the choroidal thelial ingrowth, use of this toxic to iatrogenic or postoperative periph- detachment resolved. On postopera- agent in the lamellar interface should eral retinal breaks. Recently, retinal tiveweek6,theretinaldetachmentde- be approached with caution. detachment following macular hole creased in extent, and 1 week later it surgery has been reported to resolve resolvedcompletely.Themacularhole David T. Vroman, MD spontaneously in the absence of any was closed, with visual acuity of 20/ Charleston, SC clinically detectable retinal tear.4 Sev- 200 OD. Three months later, the pa- Carol L. Karp, MD eral hypotheses were proposed: (1) tient underwent phacoemulsification Miami, Fla small occult breaks that ultimately with posterior chamber intraocular close, (2) a postsurgical temporary in- lens implantation, and visual acuity Corresponding author: Carol L. Karp, crease in fluid flow through the macu- improved to 20/50 OD. MD, Bascom Palmer Eye Institute, 900 lar hole, or (3) subretinal exudation NW 17th St, Miami, FL 33136. caused by surgery. Comment. This is the first report, to 1. Farah SG, Azar DT, Gurdal C, Wong J. Laser in our knowledge, of choroidal detach- situ keratomileusis: literature review of a devel- oping technique. J Cataract Refract Surg. 1998; Report of a Case. A 69-year-old Af- ment after macular hole surgery, con- 24:989-1006. rican American man with hyperten- current with a bullous retinal de- 2. Stein HA, Stein RM, Price C, Salim GA. Alcohol removal of the epithelium for excimer laser ab- sion and hyperlipidemia was seen for tachment that showed spontaneous 4 lation: outcomes analysis. J Cataract Refract Surg. a 1-year history of central distortion resolution. Akduman et al reported 1997;23:1160-1163. in the right eye. Best-corrected visual several cases of retinal detachment oc- 3. Agrawal VB, Hanuch OE, Bassage S, Aquavella JV. Alcohol vs mechanical epithelial debride- acuity was 20/400 OD and 20/30 OS. curring after macular hole surgery that ment: effect on underlying cornea before ex- Intraocular pressure was 14 mm Hg spontaneously resolved. The au- cimer laser surgery. J Cataract Refract Surg. 1997; in both eyes. Findings from slitlamp thors proposed that retinal detach- 23:1153-1159. examinationrevealedbilateralnuclear ment may be secondary to (1) small scleroticcataractswithcorticalspokes. occult breaks that ultimately close Fundus examination of the right eye when traction on the vitreous base Serous Retinal and revealed a stage 3 macular hole with from the intraocular gas bubble de- Choroidal Detachment After surrounding neurosensory detach- creases as the gas reabsorbs; (2) a tem- Macular Hole Surgery ment and a mild epiretinal membrane. porary increase in flow of fluid from The patient underwent pars plana vi- the vitreous cavity through the macu- One of the most serious complica- trectomy, peeling of the posterior hya- lar hole after the cortical vitreous is tions of macular hole surgery is reti- loidfromthedisctotheperipherywith surgically removed; or (3) subretinal detachment, which is usually a soft-tip silicone cannula, perifoveal nal exudation from tissue stress treated promptly with a second sur- epiretinal membrane removal using caused by the surgery.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 This patient provides strong evi- Originally described by Ryan and mented choroidal lesions symmetri- dence that the cause of retinal detach- Maumenee,1 it is characterized by cally scattered throughout the post- ment in some cases is exudative. Al- posterior segment inflammation in equatorial retina. The cause is though this is supported by its bullous the presence of multiple depig- presumed to be autoimmune and appearance, inferior localization, and shifting subretinal fluid, the coexist- ence of the retinal detachment with a choroidal detachment, both showing spontaneous resolution, reaf- firms exudation as the most likely underlying mechanism. The cause for postsurgical choroidal and subretinal exudation may be related to in- traoperative and/or perioperative transient hypotony and/or surgical tissue trauma with consequent release of chemomodulators. The only feature in this patient’s intervention that sets him apart from the usual macular hole surgery case is the considerable ef- fort required to separate the posterior hyaloid from the disc. It is possible that this played a role in causing subretinal and choroidal exudation from the optic disc and peripapillary region. This case stresses the need for close patient observation instead of an Figure 1. Fundus appearance of case 1 is consistent with a diagnosis of birdshot retinochoroidopathy. immediate reoperation when retinal detachment following macular hole A surgery does not show a clear rheg- matogenous origin. Nasal Temporal 360 µm 450 µm 200 µm 290 µm Enrique Garcia-Valenzuela, MD, PhD Dean Eliott, MD Detroit, Mich 250 µm Corresponding author: Dean Eliott, MD, Kresge Eye Institute, 4717 St Antoine, Detroit, MI 48201. 41 dB

1. Kelly NE, Wendel RT. Vitreous surgery for id- Log Reflection iopathic macular holes: result of a pilot study. Arch Ophthalmol. 1991;109:654-659. 2. Park SS, Marcus D, Duker JS, et al. Posterior segment complications after vitrectomy for macu- B OCT RETINAL THICKESS MAP (OS) lar hole. Ophthalmology. 1995;102:775-781. 3. Banker AS, Freeman WR, Kim JW, et al. Vision- Sup threatening complications of surgery for full- thickness macular holes: Vitrectomy for Macu- Nas Tem lar Hole Study Group. Ophthalmology. 1997;104: 312 1442-1453. Inf 4. Akduman L, Del Priore LV, Kaplan HJ. Sponta- neous resolution of retinal detachment occur- 485 ring after macular hole surgery. Arch Ophthal- mol. 1998;116:465-467. 258443 506 520 408

325 Intravitreal Triamcinolone

for Refractory Cystoid Center 212 Macular Edema Secondary 505±12 µm to Birdshot

Retinochoroidopathy 150 200 250 300 350 400 450 500 µm

Birdshot retinochoroidopathy is a Figure 2. Optical coherence tomograph (OCT) depicts extensive cystoid macular edema (arrows) that chronic, bilateral uveitic disorder. failed conservative therapy.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 more than 90% of patients test posi- A tive for the HLA-A29 serotype.2 Ap- proximately half of affected eyes Inferotemporal Superonasal develop cystoid macular edema (CME), and this represents a major 170 µm cause of considerable visual loss from this condition.3 A rationale for treatment with corticosteroids has been established based on the in- 250 flammatory nature of the disease. µm However, systemic and periocular corticosteroids have failed to pro- duce significant improvement in 45 dB most treated patients.4 We report 2 cases of refractory CME secondary Log Reflection to birdshot retinochoroidopathy that

were successfully treated with in- B travitreal injections of triamcino- OCT RETINAL THICKESS MAP (OS) lone acetonide. Sup

Report of Cases. Case 1. A 60-year- Nas Tem 209 old woman was diagnosed with bird- Inf shot retinochoroidopathy 3 years prior to initial examination. She was 261 positive for HLA-A29 and had a fundus appearance consistent with this 209223 203 326 271

condition (Figure 1). This in- 237 cluded multiple creamy yellow choroidal lesions posterior to the equa- tor bilaterally. The anterior vitreous Center 174 171±16 µm showed mild cells with some vitreous debris.

At initial examination, she com- 150 200 250 300 350 400 450 500 µm plained of chronic floaters with oc- casional photopsia. However, she Figure 3. Optical coherence tomograph (OCT) after intravitreal corticosteroid injection shows near noted acute blurring of vision and resolution of cystoid macular edema (arrows). distortion in the left eye during the prior 6 weeks. Her best-corrected vi- 20/60 OS and OCT showed no improved to 20/25 OS at this interval. sual acuity was 20/20 OD and 20/60 provement in CME (Figure 2). The After 6 months of follow-up, the pa- OS. Intraocular pressures were 14 patient was offered an intravitreal tri- tient maintains this level of acuity and mm Hg bilaterally. Anterior seg- amcinolone injection to treat re- has shown no recurrence of CME. ment examination findings were sidual edema. Informed consent was Macular thickness remains normal at normal with the exception of mild obtained, and the patient under- 190 µm as measured by OCT. The nuclear sclerotic cataracts. Indirect went injection of 4 mg of triamcino- greatest intraocular pressure mea- ophthalmoscopy and slitlamp bio- lone acetonide (Kenalog 40; Apoth- sured during the follow-up period microscopy showed a normal optic econ, Princeton, NJ) in 0.1 mL. The was 18 mm Hg. The patient showed disk and retinal vasculature. The injection was performed under topi- no progression of cataract during this right macula was normal, and the left cal anesthesia through the pars plana interval. macula showed intraretinal thick- inferiorly using a 27-gauge needle. Case 2. A 38-year-old woman ening involving the fovea with a cys- Immediately after the injection, the was diagnosed with birdshot reti- toid appearance. The retinal periph- patient described a transient visual nochoroidopathy on initial presen- ery showed symmetric birdshot perturbation owing to the opaque tation based on characteristic fun- lesions as described. corticosteroid compound sus- dus findings. Findings from HLA- Fluorescein angiography was pended in the vitreous cavity. This A29 testing were positive. Slitlamp obtained and showed leakage in a pet- had resolved over the next 2 days. biomicroscopy showed consider- alloid pattern involving the left fo- Within 10 days, OCT showed reduc- able neovascularization of the right vea. Optical coherence tomography tion of macular thickness to 240 µm optic disc along with venous sheath- (OCT) confirmed CME with intrareti- with improvement of visual acuity to ing. Both maculas showed trace nal thickening measured at 540 µm. 20/50 OS. At 2 months, CME re- CME. The peripheries were no- The patient was given ketoro- solved completely with a return of table for symmetric, creamy yellow lac topical drops 4 times a day. At 3 OCT macular thickness to 190 µm birdshot lesions scattered through- months, her visual acuity remained (Figure 3). Her visual acuity im- out the postequatorial region. The

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 with 0.1 mL of triamcinolone ace- A tonide (40 mg/mL) through the pars Inferonasal Superotemporal plana inferiorly. She experienced a transient visual perturbation from the opaque intravitreal corticoste- 370 µm roid suspension lasting 2 days. At 1 month, her visual acuity improved to 20/100 OD. The macular thickness was reduced to 220 µm on OCT. Her visual acuity gradually re- 250 µm covered to 20/50 OD at 3 months with a corresponding macular thickness of 140 µm on OCT (Figure 5). 36 dB At 6 months following intravitreal Log Reflection corticosteroid injection, she maintains a stable macular thickness of 140 µm and visual acuity measures B OCT RETINAL THICKESS MAP (OD) 20/30 OD without correction. Of

Sup note, neovascularization of the disc has shown regression at 6 months. Nas Tem It is unclear whether this is an ef- 319 Inf fect of prior photocoagulation and/or antiangiogenic effect from the cor- 416 ticosteroid. Intraocular pressure never exceeded 16 mm Hg during 300396 436 440 331 the follow-up interval, and there was

362 no evidence of cataract formation during this time.

Center 275 Comment. Birdshot retinochoroido- ± µ 437 42 m pathy often is seen with CME, a common cause of visual loss in this uveitic condition. Current treat- 150 200 250 300 350 400 450 500 µm ments target the inflammatory na- Figure 4. Optical coherence tomograph (OCT) confirms intraretinal thickening consistent with cystoid ture of the disorder. Corticoste- macular edema that also failed conservative therapy (arrows). roids represent the mainstay of therapy, but systemic and periocu- vitreous showed 1+ cells bilater- though the left macula showed mild lar routes of administration have ally. Panretinal photocoagulation CME, she had remained essentially produced disappointing results was performed on the right eye, and stable in this eye and was not symp- in controlling inflammation and the patient was followed clinically tomatic until visual loss occurred on preserving visual acuity. Cyclospor- for 3 years with stable visual acuity the right. ine A has shown promise owing to at the 20/40 level. Fluorescein angiography con- its potent immunosuppressive On an emergency visit, the pa- firmed leakage from disc neovascu- effect, but its role has not been fully tient reported acute visual loss in the larization as well as CME in a pet- established in birdshot retinocho- right eye accompanied by central dis- alloid pattern. The OCT measured roidopathy.4,5 Two patients are de- tortion during the prior week. Her the intraretinal thickening at 290 scribed who had CME that re- best-corrected visual acuity mea- µm. The patient was treated with fur- sponded promptly to intravitreal sured 20/400 OD and 20/60 OS. In- ther panretinal photocoagulation administration of triamcinolone ace- traocular pressures were 12 mm Hg and a sub-Tenon injection of triam- tonide, an injectable corticosteroid and 15 mm Hg, respectively. The an- cinolone acetonide (40 mg/mL). At suspension. Both showed marked terior segments were normal with 1-month follow-up, her visual acu- improvement in macular thickness the exception of rare cells in each an- ity remained at 20/200 OD. The with a corresponding dramatic in- terior chamber. Examination of the CME showed no response to therapy crease in visual acuity maintained for anterior vitreous revealed 2+ cells on and actually increased to 370 µm on 6 months of follow-up. the right and 1+ cells on the left. OCT (Figure 4). The patient was The rationale for intravitreal Fundus examination of the right eye followed up for 1 additional month corticosteroids parallels that estab- showed persistent disc neovascular- without a clinical response. At this lished for other routes of corticoste- ization with a band of new prereti- time, she was offered an intravit- roid administration, specifically the nal hemorrhage beneath the infero- real triamcinolone injection to treat anti-inflammatory effect. However, temporal arcade. The right macula residual edema. After obtaining in- the intravitreal route alleviates the showed considerable CME. Al- formed consent, she was injected pharmacologic issues of penetra-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 edema temporally, with recovery A of retinal function after restoration Temporal Nasal of structural integrity. The dura- tion of effect exceeds 6 months in both treated patients. Further study is warranted to evaluate the long-term risks and benefits asso- 140 µm ciated with this promising treatment modality for CME complicat- ing birdshot retinochoroidopathy. 250 µm Adam Martidis, MD Jay S. Duker, MD

47 dB Carmen A. Puliafito, MD Log Reflection Boston, Mass

Corresponding author: Jay S. Duker, B OCT RETINAL THICKESS MAP (OD) MD, 750 Washington St, Box 450,

Sup Boston, MA 02111.

Nas Tem 1. Ryan SJ, Maumenee AE. Birdshot retinocho- 251 roidopathy. Am J Ophthalmol. 1980;79:31-45. Inf 2. Nussenblatt RB, Mittal KK, Ryan S. Birdshot retinochoroidopathy associated with HLA-A29 216 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol. 1982;84:147- 158. 229207 126 215 521 3. Duker JS. Birdshot retinochoroidopathy. In: Guyer DR, Yannuzzi LA, Chang S, Shields JA, 238 Green WR, eds. Retina-Vitreous-Macula. Phila- delphia, Pa: WB Saunders Co; 1999:565-568. 4. Vitale AT, Rodriguez A, Foster CS. Low-dose cy- Center 229 closporine therapy in the treatment of birdshot 106±7 µm retinochoroidopathy. Ophthalmology. 1994;101: 822-831. 5. LeHoang P, Girard B, Deray G, et al. Cyclospor- ine in the treatment of birdshot retinochoroido- 150 200 250 300 350 400 450 500 µm pathy. Transplant Proc. 1988;20(3, suppl 4):128- 130. 6. Danis RP, Ciulla TA, Pratt LM, Anliker W. In- Figure 5. Optical coherence tomograph (OCT) after intravitreal corticosteroid confirms resolution of travitreal triamcinolone acetonide in exudative cystoid macular edema (arrows). age-related macular degeneration. Retina. 2000; 20:244-250. 7. Challa JK, Gillies MC, Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular de- tion and bioavailability. A potent intervention may best be reserved for generation and intravitreal triamcinolone: 18 dose of medication is delivered di- those truly refractory cases that have month follow-up. AustNZJOphthalmol. 1998; rectly to its site of action with a rapid failed standard topical, regional, and 26:277-281. onset. With this more aggressive ap- oral routes of delivery. Of note, nei- proach, concerns arise regarding ad- ther treated patient experienced any verse events associated with the cor- adverse effects related to the drug or ticosteroid medication and the the injection procedure. Both expe- Exudative Retinal injection procedure. rienced transient visual distur- Detachment in Specifically, corticosteroids bance lasting a few days owing to the Behc¸et Disease have been associated with a rise in opaque nature of triamcinolone sus- intraocular pressure as well as the pended in the vitreous cavity. The Behc¸et disease is a systemic vascu- development of cataracts. All routes risks seem justified based on the litis of uncertain cause. Ocular in- of corticosteroid administration failure of more conservative ap- flammation is 1 of 4 clinical criteria share these risks, although the risk proaches in the presence of progres- on which the diagnosis is based. An- may be theoretically amplified with sive visual loss. terior uveitis and occlusive retinal injection into the eye. The injec- Intravitreal corticosteroid in- vasculitis with or without retinitis tion procedure itself introduces jection seems to be a viable option- are characteristic. Rhegmatog- unique risks of endophthalmitis, for the treatment of refractory enous retinal detachment has been retinal detachment, and hemor- CME owing to birdshot retinocho- reported.1,2 An unspecified type of rhage. Larger studies of corticoste- roidopathy. Preliminary results retinal detachment was observed roid injections for other conditions show prompt resolution of edema subsequent to severe necrotizing have not shown significant morbid- with corresponding improved vi- retinitis.3 ity associated with the intravitreal in- sual acuity. Improvement in visual This report describes 2 pa- jection procedure.6,7 However, this acuity lags resolution of macular tients who developed exudative reti-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 were in the fovea. The retinal ves- sels and optic nerve were normal. In- travenous fluorescein angiography of both eyes showed no serious vascular perfusion defects. The patient received a subtenon steroid injection and oral prednisone (60 mg). He was admit- ted the following morning to re- ceive intravenous methylprednisolone, 1 g daily. Azathioprine, 150 mg daily, was also started. Three days later, there was considerable vitreous clearing and subretinal fluid resolution. Hemorrhagic vasculitis was more visible (Figure 2). Indo- cyanine green angiography findings were normal. Human leuko- Figure 1. Yellow subretinal material in the macula and retinal hemorrhage in the inferonasal quadrant cyte antigen testing was positive for characterize the exudative retinal detachment in the right eye of case 1. HLA B51 antigen. Findings from chest radiography, PPD (purified protein derivative), fluorescent ti- ter antibody-antibody screen, an- giotensin-converting enzyme, complete blood cell count, chemistry panel, and urinalysis were normal. Prescriptions at discharge included prednisone, 60 mg daily, and azathioprine, 150 mg daily. Panuveitis without ERD recurred in the right eye 4 months later owing to non- compliance with administration of medication. Resumption of med- ications controlled the recurrence. No additional ocular recurrences developed. Prednisone was slowly tapered to 10 mg, azathioprine was increased to 200 mg, and cochi- cine, alendronate sodium, and cal- Figure 2. Hemorrhagic vasculitis was more evident inferonasal quadrant of the left eye as the vitreitis cium were added. Twenty-three cleared (case 1). months later, visual acuity was 20/ 400 OD and 20/30 OS. Foveal retinal detachment (ERD) during the cluded painful oral and genital ul- nal pigment epithelial clumping was course of Behc¸et disease. One had an cers and nodular rashes on the lower present more prominently in the unusual pseudohypopyon in the extremities. He denied tinnitus, right eye. There were no residual subretinal space. Both ERDs were re- headache, stiff neck, viral illness, viti- exudates. current and associated with hemor- ligo, ocular trauma, and arthritis. Case 2. A 60-year-old African rhagic retinal vasculitis. Visual acuity was counting fin- American woman was seen for reti- gers at 1 foot OD and 20/400 OS. nal consultation. She had a 12-year Report of a Case. Case 1. A 24-year- Biomicroscopic examination re- history of multiple emergency de- old Albanian man developed acute, vealed 4+ anterior chamber cells, mi- partment visits and hospital admis- painful, severe visual loss in his right crohypopyon visible with gonios- sions for uveitis diagnosed previ- eye. Similar episodes had occurred copy, and posterior synechiae in the ously as toxoplasma retinitis, possible in both eyes during the preceding 6 right eye. The vitreous was hazy and Behc¸et disease, and sarcoidosis. Treat- months. Pain and redness resolved cellular. Exudative retinal detachment included 3 admissions for in- spontaneously within a few weeks, ment with sheets of yellowish sub- travenous steroids, multiple courses and visual acuity improved over sev- retinal material extended into the of topical steroid drops, and several eral months. Previous treatment in- macula (Figure 1). There was a 3- to 6-month courses of oral pred- cluded topical steroids for uveitis sheathed inferonasal vessel with as- nisone. Each recurrence caused ad- with subretinal fluid. His medical sociated hemorrhage. Left eye ante- ditional visual loss. Her medical his- history was unremarkable. Positive rior segment and vitreous were quiet. tory was notable for a Ghon complex findings on systems review in- Yellow subretinal linear deposits on chest radiography, isoniazid-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 induced hepatitis, and osteoporosis. Systems review revealed painful genital and oral ulcers but no arthritis, headache or central nervous system disease, tinnitus, vitiligo, or skin rashes. Abnormal test results included positive PPD without an- ergy, positive toxoplasma enzyme im- munosorbent assay, occlusive vasculitis on intravenous fluorescein angiography, and reduced flow in the left posterior ciliary artery and both ophthalmic arteries on color Doppler ultrasonography. Angioten- sin-converting enzyme, gallium scan, and cerebrospinal fluid examination findings were normal. Human leukocyte antigens included HLA A28, B70, and Bw6. Figure 3. B-scan ultrasound of case 2 revealed exudative retinal detachment. Medical records revealed that ERDs were recognized on 2 occa- sions in the left eye. In December 1987, 1 month after a 10-month oral prednisone tapering treatment for papillitis and panuveitis in the right eye, visual loss, redness, pain, hy- popyon iritis, and vitreitis developed in the left eye. B-scan ultrasonography demonstrated ERD (Figure 3). Inflammation was controlled, and the ERD resolved with intravenous steroids, but visual acuity was counting fingers. In January 1992, pain, redness, and visual loss developed in the left eye after a 2-year period marked by bilateral cataract extraction and recurrent asymptomatic inflammatory branch vein occlusions treated with Figure 4. Recurrent exudative retinal detachment with pseudohypopyon in case 2. intermittent oral, topical, and subtenon steroids. Clinical examination revealed panuveitis and recurrent itides, including Vogt-Koyanagi- Spontaneous remissions fol- ERD with an unusual pseudohypo- Harada (VKH) disease, sympathetic lowing sudden and severe exacer- pyon in the left eye (Figure 4). Ocu- ophthalmia, posterior scleritis, and bations characterize Behçet uveitis. lar inflammation and ERD resolved sarcoidosis, but has not been de- Spontaneous remissions may be during a 4-month course of oral pred- scribed in Behçet disease. Unlike misinterpreted as indications of a nisone. Visual acuity was hand mo- most other entities, ERDs in Behçet self-limited or benign process or tions. Multiple relapses at 2- to diseases were recurrent and associ- that subtherapeutic amounts of ste- 6-month intervals were managed with ated with hemorrhagic retinal vas- roid have controlled the disease. intermittent subtenon injections, ste- culitis. Inaccurate or delayed diagnosis roid drops, and short courses of oral The visual outcome in Behçet may impede timely, appropriately prednisone. In November 1994, Beh- ERDs ranged from prolonged, aggressive, long-term administra- çet disease was diagnosed, and sys- gradual recovery to no recovery af- tion of immunosuppressive agents temic immunosuppression was ini- ter each relapse. One important goal needed to prevent recurrences and tiated. The patient has remained of treatment therefore must be to blindness.4 relapse free with visual acuity of 20/60 prevent relapses with long-term im- Behçet ERD may be differenti- OD and hand motions OS. munosuppression rather than to re- ated from other posterior uveitides. spond to ERDs after they develop. Recurrent ERDs are unusual in VKH Comment. The differential diagno- Single or recurrent exacerbations disease in which ERD typically oc- sis of ERD should include Behçet may cause irreversible visual acuity curs during an initial attack that is fol- disease. Exudative retinal detach- or visual field loss despite treat- lowed by anterior segment inflam- ment may complicate posterior uve- ment. mation. Hemorrhagic vasculitis is not

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 a characteristic feature of VKH dis- cially if it is recurrent or associated 900 Walnut St, Philadelphia, PA ease, sympathetic ophthalmia, or pos- with hemorrhagic retinal vasculitis. 19107 (e-mail: [email protected]). terior scleritis, although it may com- 1. Amatsu M, Kubota K. Idiopathic detachment of plicate sarcoidosis. Also, ocular Tamara R. Vrabec, MD the retina developed in a case of Behçet’s disease. Nippon Ganka Kiyo. 1969;20:249-252. inflammation often is not the pre- Philadelphia, Pa 2. Akova YA, Yilmaz G, Aydin P. Retinal tears as- senting manifestation of Behçet dis- sociated with panuveitis and Behçet’s disease. ease, occurring initially in only 8.6% This study was supported in part by Ophthalmic Surg Lasers. 1999;30:762-765. 4,5 3. Colvard M, Robertson DM, O’Duffy D. The ocu- to 34% of patients. Thorough sys- the Eye Research Institute, Philadel- lar manifestations of Behçet’s disease. Arch Oph- tems review is of utmost importance phia. thalmol. 1988;95:1813-1817. 4. Mishima S, Masuda K, Izawa Y, Mochizuki M, when Behçet disease is suspected. Hu- I thank Gloria Parker, library Namba K. The eighth Frederick H. Verhoeff lec- man leukocyte antigen testing may technician, Wills Eye Hospital, for her ture. Trans Am Ophthalmol Soc. 1979;77:225-279. support the diagnosis. Behçet dis- assistance. 5. Barra C, Belfort R Jr, Abreu MT, et al. Behçet’s disease in Brazil: a review of 49 cases with em- ease should be considered in the dif- Corresponding author: Tamara phasis on ophthalmic manifestations. Jpn J Oph- ferential diagnosis of ERD, espe- R. Vrabec, MD, Wills Eye Hospital, thalmol. 1991;35:339-346.

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